cancers Review Diabetes and Pancreatic Cancer—A Dangerous Liaison Relying on Carbonyl Stress Stefano Menini 1,† , Carla Iacobini 1,†, Martina Vitale 1, Carlo Pesce 2 and Giuseppe Pugliese 1,* 1 Department of Clinical and Molecular Medicine, “La Sapienza” University, 00189 Rome, Italy; [email protected] (S.M.); [email protected] (C.I.); [email protected] (M.V.) 2 Department of Neurosciences, Rehabilitation, Ophtalmology, Genetic and Maternal Infantile Sciences (DINOGMI), Department of Excellence of MIUR, University of Genoa Medical School, 16132 Genoa, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-03-3377-5440 † These authors contributed equally to this work. Simple Summary: Diabetic people have an increased risk of developing several types of cancers, particularly pancreatic cancer. The higher availability of glucose and/or lipids that characterizes diabetes and obesity is responsible for the increased production of highly reactive carbonyl com- pounds, a condition referred to as “carbonyl stress”. Also known as glycotoxins and lipotoxins, these compounds react quickly and damage various molecules in cells forming final products termed AGEs (advanced glycation end-products). AGEs were shown to markedly accelerate tumor development in an experimental model of pancreatic cancer and AGE inhibition prevented the tumor-promoting effect of diabetes. In humans, carbonyl stress has been associated with the risk of pancreatic cancer and recognized as a possible contributor to other cancers, including breast and colorectal cancer. These findings suggest that carbonyl stress is involved in cancer development and growth and may be the mechanistic link between diabetes and pancreatic cancer, thus representing a potential drug target. Abstract: Citation: Menini, S.; Iacobini, C.; Both type 2 (T2DM) and type 1 (T1DM) diabetes mellitus confer an increased risk of Vitale, M.; Pesce, C.; Pugliese, G. pancreatic cancer in humans. The magnitude and temporal trajectory of the risk conferred by Diabetes and Pancreatic Cancer—A the two forms of diabetes are similar, suggesting a common mechanism. Carbonyl stress is a Dangerous Liaison Relying on hallmark of hyperglycemia and dyslipidemia, which accompanies T2DM, prediabetes, and obesity. Carbonyl Stress. Cancers 2021, 13, 313. Accumulating evidence demonstrates that diabetes promotes pancreatic ductal adenocarcinoma https://doi.org/10.3390/cancers1302 (PDAC) in experimental models of T2DM, a finding recently confirmed in a T1DM model. The 0313 carbonyl stress markers advanced glycation end-products (AGEs), the levels of which are increased in diabetes, were shown to markedly accelerate tumor development in a mouse model of Kras-driven Received: 14 December 2020 PDAC. Consistently, inhibition of AGE formation by trapping their carbonyl precursors (i.e., reactive Accepted: 14 January 2021 carbonyl species, RCS) prevented the PDAC-promoting effect of diabetes. Considering the growing Published: 16 January 2021 attention on carbonyl stress in the onset and progression of several cancers, including breast, lung and colorectal cancer, this review discusses the mechanisms by which glucose and lipid imbalances Publisher’s Note: MDPI stays neu- tral with regard to jurisdictional clai- induce a status of carbonyl stress, the oncogenic pathways activated by AGEs and their precursors ms in published maps and institutio- RCS, and the potential use of carbonyl-scavenging agents and AGE inhibitors in PDAC prevention nal affiliations. and treatment, particularly in high-risk diabetic individuals. Keywords: pancreatic ductal adenocarcinoma; hyperglycemia; obesity; reactive carbonyl species; methylglyoxal; receptor for advanced glycation end-products; carnosine derivatives; yes-associated Copyright: © 2021 by the authors. Li- protein; epithelial growth factor receptor censee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and con- ditions of the Creative Commons At- 1. Introduction tribution (CC BY) license (https:// creativecommons.org/licenses/by/ Pancreatic cancer is a highly fatal malignancy with very poor overall survival rates. 4.0/). Pancreatic ductal adenocarcinoma (PDAC) is by far the most common and most lethal type Cancers 2021, 13, 313. https://doi.org/10.3390/cancers13020313 https://www.mdpi.com/journal/cancers Cancers 2021, 13, 313 2 of 26 of pancreatic cancer, representing over 90% of the pancreatic malignancies [1]. According to the latest data from the Surveillance, Epidemiology, and End Results Program, the five-year survival rate for people with PDAC is 9% [2]. Because of the poor survival outcomes, PDAC is the seventh leading cause of global cancer death despite being the 10th most common incident cancer [3] and is projected to become the second leading cause of neoplasia-related deaths in the USA in the next two decades [4], in parallel with the rising prevalence of risk factors such as obesity and diabetes. The main causes of these dismal outcomes and prospects are multifactorial in nature; as no simple early detection methods exists, PDAC patients are predominantly elderly people in overall poor health, and PDAC tumors have the ability to rapidly develop acquired resistance to therapies. What is more, the peculiar ability of PDAC to metastasize early in the disease course limits the effectiveness of surgery and radiation [5]. Therefore, in the absence of effective and efficient diagnostic and therapeutic tools, it is important to focus on prevention by eliminating modifiable risk factors associated with PDAC or, at least, defuse the threat they pose by identifying the molecular mechanisms underlying their PDAC-promoting activity. Among these risk factors, diabetes mellitus has been shown to have a remarkable association with PDAC [6]. Driven by the pandemic of obesity, diabetes is a growing global public health issue contributing to premature mortality, morbidity, and disability [7]. Diabetes prevalence is steadily increasing everywhere, particularly in the world’s middle-income countries [8]. The number of adults living with this metabolic disease increased from 108 million in 1980 to 422 million in 2014 and is predicted to rise to 642 million by 2040 [9] (i.e., over 10% of the global population). According to the American Diabetes Association defini- tion, diabetes mellitus is a group of chronic metabolic diseases characterized by abnormal metabolism of carbohydrates secondary to defects in insulin secretion, action, or both, resulting in high levels of glucose in the blood [10]. Type 2 diabetes mellitus (T2DM) is the most prevalent form of diabetes, accounting for 90–95% of diabetic patients. Often associated with overweight and obesity, hyperglycemia is the result of resistance to insulin action combined with inadequate insulin secretion [11]. Formerly known as juvenile-onset diabetes or insulin-dependent diabetes, Type 1 diabetes mellitus (T1DM) accounts for less than 10% of diabetic patients and is characterized by an absolute deficiency of insulin se- cretion due to immune-mediated destruction of the insulin-producing β-cells of pancreatic islets [10]. In addition to these etiological distinctions, important metabolic differences exist between T1DM and T2DM, as dyslipidemia and hypertension often pre-date diagnosis and accompany T2DM, but usually not T1DM. In the same way, hyperglycemia, which is the common factor of the two forms of diabetes, can arise a long time before T2DM diagno- sis. The Centers for Disease Control and Prevention estimates that in the USA, for every known case of diabetes, there is one undiagnosed case of T2DM and one with prediabetes (i.e., impaired fasting glucose or impaired glucose tolerance) [11]. This observation has important clinical implications since the toxic effects of glucose may induce pathological and functional changes in different body tissues and organs in the absence of overt clinical symptoms [10]. Along with hyperglycemia, its consequences are also shared by the two forms of diabetes, as chronic complications such as cardiovascular and kidney disease, vision loss, and neurological deficits affect both T1DM and T2DM patients in the long run [12]. Finally, both T2DM and T1DM have been increasingly recognized as risk factors for the development of various cancers, including PDAC [6,13–16]. Following a brief presentation of the complex dual relationship between pancreatic cancer and diabetes, this review will summarize the epidemiological data and experimental evidence on T1DM and T2DM as risk factors for PDAC. In particular, the mechanisms by which glucose and lipid imbalances drive diabetes-associated carbonyl stress, the role of carbonyl stress in cancer, especially PDAC, and the potential use of carbonyl-scavenging agents in PDAC prevention/treatment in high-risk diabetic individuals will be discussed in detail. Though diabetes has been recently identified as possible risk factor for other types of pancreatic cancer, particularly the intraductal papillary mucinous neoplasm of the Cancers 2021, 13, x 3 of 26 scavenging agents in PDAC prevention/treatment in high-risk diabetic individuals will be Cancers 2021, 13, 313 discussed in detail. Though diabetes has been recently identified as possible risk factor3 of for 26 other types of pancreatic cancer, particularly the intraductal papillary mucinous neoplasm of the pancreas [17] and pancreatic neuroendocrine tumors [18], the amount of available pancreasdata on the [17 ]relationship and pancreatic